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Increased incidence of hand, foot and mouth disease (HFMD) has been recognized as a critical challenge to communicable disease control and public health response. This study aimed to quantify the association between climate variation and notified cases of HFMD in selected cities of Shanxi Province, and to provide evidence for disease control and prevention. Meteorological variables and HFMD cases data in 4 major cities (Datong, Taiyuan, Changzhi and Yuncheng) of Shanxi province, China, were obtained from the China Meteorology Administration and China CDC respectively over the period 1 January 2009 to 31 December 2013. Correlations analyses and Seasonal Autoregressive Integrated Moving Average (SARIMA) models were used to identify and quantify the relationship between the meteorological variables and HFMD. HFMD incidence varied seasonally with the majority of cases in the 4 cities occurring from May to July. Temperatures could play important roles in the incidence of HFMD in these regions. The SARIMA models indicate that a 1° C rise in average, maximum and minimum temperatures may lead to a similar relative increase in the number of cases in the 4 cities. The lag times for the effects of temperatures were identified in Taiyuan, Changzhi and Yuncheng. The numbers of cases were positively associated with average and minimum temperatures at a lag of 1 week in Taiyuan, Changzhi and Yuncheng, and with maximum temperature at a lag of 2 weeks in Yuncheng. Positive association between the temperature and HFMD has been identified from the 4 cities in Shanxi Province, although the role of weather variables on the transmission of HFMD varied in the 4 cities. Relevant prevention measures and public health action are required to reduce future risks of climate change with consideration of local climatic conditions., Author Summary Understanding of the impact of weather variables on HFMD transmission remains limited due to various local climatic conditions, socioeconomic status and demographic characteristics in different regions. This study provides quantitative evidence that the incidence of HFMD cases was significantly associated with temperature in Shanxi Province, North China. The delayed effects of weather variables on HFMD dictate different public health responses in 4 major cities in Shanxi Province. The results may provide a direction for local community and health authorities to perform public health actions, and the SARIMA models are helpful in the prediction of epidemics, determination of high-risk areas and susceptible populations, allocation of health resources, and the formulation of relevant prevention strategies. In order to reduce future risks of climatic variations on HFMD epidemics, similar studies in other geographical areas are needed, together with a longer study period to enable trend analysis which takes into consideration local weather conditions and demographic characteristics.